Birth weight associations with psychiatric and physical health, cognitive function, and DNA methylation differences in an adult population

Madden, Rebecca A; McCartney, Daniel L.; Martin, Richard M; Hillary, Robert F.; Bermingham, Mairead Lesley; Rawlik, Konrad; Morris, Stewart W.; Campbell, Archie; Porteous, David J.; Deary, Ian J.; Evans, Kathryn; Hafferty, Jonathan D.; McIntosh, Andrew M.; Marioni, Riccardo E.

doi:10.1101/664045

Cited by 12 publications

(9 citation statements)

References 45 publications

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“…The present study includes analysis on methylation data from 2,578 unrelated individuals in the first set (referred to herein as set 1) and 4,450 unrelated individuals in the second set (set 2). Quality control steps for both sets have been fully reported previously (37). Briefly, ShinyMethyl was used to plot the logmedian intensity of methylated versus un-methylated signal per array and outliers were excluded upon visual inspection (38).…”

Section: Methodsmentioning

confidence: 99%

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

Stevenson

McCartney

Hillary

et al. 2019

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Results from large cohort studies investigating the association between inflammation and cognition have been mixed, possibly due to methodological disparities. However, a key issue in research utilising inflammatory biomarkers is their typically phasic responses. C-reactive protein (CRP) is widely used to investigate the association between chronic inflammation and cognition, but its plasma concentrations can markedly deviate in response to acute infection. Recently a large-scale epigenome-wide association study identified DNA methylation correlates of CRP. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. Here, we generate an epigenetic CRP score and investigate its trajectories with age, and associations with cognitive ability, in comparison to serum CRP in two cohorts: a longitudinal study of older adults (the Lothian Birth Cohort 1936, n=889) and a large, cross-sectional cohort (Generation Scotland, n=7,028).We identified differing trajectories of serum CRP across the cohorts, with no homogeneous trends seen with age. Conversely, the epigenetic score was consistently found to increase with age, and to do so more rapidly in males compared to females. Higher levels of serum CRP were found to associate with poorer cognition in Lothian Birth Cohort 1936, but not in Generation Scotland. However, a consistent negative association was identified between cognition and the epigenetic score in both cohorts. Furthermore, the epigenetic score accounted for a greater proportion of variance in cognitive ability.Our results suggest that epigenetic signatures of acute inflammatory markers may provide an enhanced signature of chronic inflammation, allowing for more reliable stratification of individuals, and thus clearer inference of associations with incident health outcomes.

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Section: Methodsmentioning

confidence: 99%

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

Stevenson

McCartney

Hillary

et al. 2019

Preprint

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“…CpGs with missing values, non-CpG probes and non-autosomal probes were additionally removed. Quality control steps for set 2 have also been reported previously and were near identical to the set 1 protocol (28).…”

Section: Methodsmentioning

confidence: 91%

Creating and validating a DNA methylation-based proxy for Interleukin-6

Stevenson

Gadd

Hillary

et al. 2020

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Chronic inflammation is a pervasive feature of ageing and may be linked to age-related cognitive decline. However, population studies evaluating its relationship with cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. The epigenetic mechanism DNA methylation has shown utility in indexing environmental exposures and could potentially be leveraged to provide proxy signatures of chronic inflammation. We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 895 older adults (mean age: 69 years) to develop a DNA methylation-based predictor. The predictor was tested in an independent cohort (n=7,028 [417 with measured IL-6], mean age: 51 years).We examined the association between the DNA methylation IL-6 score and serum IL-6, its association with age and established correlates of circulating IL-6, and with cognitive ability. A weighted score from 12 DNA methylation sites optimally predicted IL-6 (independent test set R2=5.1%). In the independent test cohort, both measured IL-6, and the DNA methylation proxy, increased as a function of age (serum IL-6: n=417, β=0.02, SE=0.004 p=1.3x10-7; DNAm IL-6 score: n=7,028, β=0.02, SE=0.0009, p<2x10-16). Serum IL-6 was not found to associate with cognitive ability (n=417, β=-0.06, SE=0.05, p=0.19); however, an inverse association was identified between the DNA methylation score and cognitive functioning (n=7,028, β=-0.14, SE=0.02, pFDR=1.5x10-14). These results suggest DNA methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for reliable insights into the relationship between chronic inflammation and pertinent health outcomes.

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“…Whole blood DNAm was profiled using the Infinium MethylationEPIC BeadChip (Illumina Inc., San Diego, California) in 9778 participants across two processing sets (set 1 N=5,190 (comprised related individuals), set 2 N=4,583 (comprised unrelated (to each other and to set 1) individuals)) and quality controls were carried out using standard methods outlined in supplementary methods as described previously (41,42). The final DNAm dataset comprised data for 5,087 individuals in set 1 and 4,450 individuals in set 2.…”

Section: Methodsmentioning

confidence: 99%

Associations between alcohol use and accelerated biological ageing

Bøstrand

Vaher

Nooij

et al. 2020

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BackgroundHarmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates.MethodsFirst, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (AUDIT scores), and accelerated brain and epigenetic ageing in 20,258 and 8,051 individuals, respectively. Second, we used Mendelian randomization to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing.ResultsAlcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β=0.053, p=3.16×10−13; AUDIT-P: β=0.052, p=1.6×10−13; total AUDIT score: β=0.062, p=5.52×10−16; units/week: β=0.078, p=2.20×10−16), and DNA methylation GrimAge (Units/week: β=0.053, p=1.48×10− 7) and PhenoAge (Units/week: β=0.077, p=2.18×10−10). Mendelian randomization analyses revealed some evidence for a causal effect of AUD on accelerated brain ageing (β=0.272, p=0.044), and no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing.ConclusionsWe provide consistent phenotypic evidence linking alcohol use with accelerated biological ageing. There is possible evidence for a causal effect of AUD on brain age, but not for any other alcohol-related trait on brain or epigenetic age acceleration. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.

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Birth weight associations with psychiatric and physical health, cognitive function, and DNA methylation differences in an adult population

Abstract: 1Background: 2 2

Cited by 12 publications

References 45 publications

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

Creating and validating a DNA methylation-based proxy for Interleukin-6

Associations between alcohol use and accelerated biological ageing

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